What is the aim of this review?
We wanted to find out whether nutritional supplements or special diets are effective in treating foot ulcers in people with diabetes. Researchers from Cochrane collected and analysed all relevant studies (randomised controlled trials (RCTs)) to answer this question and found nine studies for inclusion. RCTs are medical studies where the treatment or care people receive is are chosen at random. This type of trial provides the most reliable health evidence about whether different approaches to treatment or care make a difference.
Of the nine studies that we identified, eight reported the outcomes we were interested in, primarily impact on ulcer healing. Findings from five studies showed very low-certainty evidence regarding the effect of oral nutritional supplements in tablet form on the healing of foot ulcers in people with diabetes. These five studies did not measure healing in such a way that we could be certain of the results, and they did not have enough participants for us to be certain of the effects. The results of three other studies also showed very low-certainty evidence as to whether nutritional supplements in other forms have any impact on ulcer healing. Two of these studies showed very low-certainty evidence as to whether nutritional supplement drinks have any impact on other outcomes such as death, likelihood of amputation, reduction in numbers of new ulcers, or people's quality of life. These studies were not well conducted and did not have enough participants involved for us to be certain of the effects.
What was studied in the review?
People with diabetes can develop foot ulcers. These are often due to reduced blood supply, reduced sensation, foot deformity, the presence of trauma, or a combination of all or some of these causes. Foot ulcers are a serious complication of diabetes and can result in serious consequences such as amputation.
It is thought that foot ulcers, like other wounds, heal better, and more quickly, if people are well-nourished. Food supplements containing certain vitamins and protein can be given to people with foot ulcers and diabetes to help to treat their wounds.
What are the main results of the review?
We found nine relevant studies dating from 2004 to 2019, involving 629 participants, 72% were men, aged, on average, 59.2 years. Most studies took place in hospital outpatient clinics. Three studies explored a different nutritional supplement drink and compared this with a drink that looked the same but did not have any added nutritional supplement. Five studies explored the effects of different types of nutritional tablets and compared these with tablets that did not contain any active ingredient, or nutritional supplement. One study compared two different doses of a vitamin D injection. One study did not report any of the outcomes of interest for this review.
Two of the studies were sponsored by the manufacturers of the nutritional supplement, five studies were sponsored by Iranian university research funding.
Findings from eight studies are unclear as to whether nutritional interventions improve the healing of foot ulcers in people with diabetes compared with no nutritional supplementation, or compared with a different dose of nutritional supplementation. One study reported adverse events and two studies reported numbers of amputations. Results are unclear as to whether there is a difference in the numbers of amputations or deaths between nutritional supplementation and no nutritional supplementation. It is also unclear if there is a difference in health-related quality of life or number of ulcers that recur between nutritional supplementation and no nutritional supplementation.
Overall, we judged the certainty of the evidence to be very low. None of the studies had enough participants, five did not measure outcomes in such a way that we could be certain of the results and the studies were not well conducted, so we are not very confident in the results. Additional studies at low risk of bias and of high-certainty evidence are needed to clarify the role of nutritional interventions for the treatment of foot ulcers in people with diabetes.
How up to date is this review?
We searched for studies that had been published up to March 2020.
Evidence for the impact of nutritional interventions on the healing of foot ulcers in people with diabetes compared with no nutritional supplementation, or compared with a different dose of nutritional supplementation, remains uncertain, with eight studies showing no clear benefit or harm. It is also uncertain whether there is a difference in rates of adverse events, amputation rate, development of new foot ulcers, or quality of life, between nutritional interventions and placebo. More research is needed to clarify the impact of nutritional interventions on the healing of foot ulcers in people with diabetes.
Foot ulcers in people with diabetes are non-healing, or poorly healing, partial, or full-thickness wounds below the ankle. These ulcers are common, expensive to manage and cause significant morbidity and mortality. The presence of a wound has an impact on nutritional status because of the metabolic cost of repairing tissue damage, in addition to the nutrient losses via wound fluid. Nutritional interventions may improve wound healing of foot ulcers in people with diabetes.
To evaluate the effects of nutritional interventions on the healing of foot ulcers in people with diabetes.
In March 2020 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting.
We included randomised controlled trials (RCTs) that evaluated the effect of nutritional interventions on the healing of foot ulcers in people with diabetes.
Two review authors, working independently, assessed included RCTs for their risk of bias and rated the certainty of evidence using GRADE methodology, using pre-determined inclusion and quality criteria.
We identified nine RCTs (629 participants). Studies explored oral nutritional interventions as follows: a protein (20 g protein per 200 mL bottle), 1 kcal/mL ready-to-drink, nutritional supplement with added vitamins, minerals and trace elements; arginine, glutamine and β-hydroxy-β-methylbutyrate supplement; 220 mg zinc sulphate supplements; 250 mg magnesium oxide supplements; 1000 mg/day omega-3 fatty acid from flaxseed oil; 150,000 IU of vitamin D, versus 300,000 IU of vitamin D; 250 mg magnesium oxide plus 400 IU vitamin E and 50,000 IU vitamin D supplements. The comparator in eight studies was placebo, and in one study a different dose of vitamin D.
Eight studies reported the primary outcome measure of ulcer healing; only two studies reported a measure of complete healing. Six further studies reported measures of change in ulcer dimension, these studies reported only individual parameters of ulcer dimensions (i.e. length, width and depth) and not change in ulcer volume.
All of the evidence identified was very low certainty. We downgraded it for risks of bias, indirectness and imprecision.
It is uncertain whether oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements, increases the proportion of ulcers healed at six months more than placebo (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.42 to 1.53). It is also uncertain whether arginine, glutamine and β-hydroxy-β-methylbutyrate supplement increases the proportion of ulcers healed at 16 weeks compared with placebo (RR 1.09, 95% CI 0.85 to 1.40).
It is uncertain whether the following interventions change parameters of ulcer dimensions over time when compared with placebo; 220 mg zinc sulphate supplement containing 50 mg elemental zinc, 250 mg magnesium oxide supplement, 1000 mg/day omega-3 fatty acid from flaxseed oil supplement, magnesium and vitamin E co-supplementation and vitamin D supplementation. It is also uncertain whether 150,000 IU of vitamin D, impacts ulcer dimensions when compared with 300,000 IU of vitamin D.
Two studies explored some of the secondary outcomes of interest for this review. It is uncertain whether oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements, reduces the number of deaths (RR 0.96, 95% CI 0.06 to 14.60) or amputations (RR 4.82, 95% CI 0.24 to 95.88) more than placebo. It is uncertain whether arginine, glutamine and β-hydroxy-β-methylbutyrate supplement increases health-related quality of life at 16 weeks more than placebo (MD −0.03, 95% CI −0.09 to 0.03). It is also uncertain whether arginine, glutamine and β-hydroxy-β-methylbutyrate supplement reduces the numbers of new ulcers (RR 1.04, 95% CI 0.71 to 1.51), or amputations (RR 0.66, 95% CI 0.16 to 2.69) more than placebo.
None of the included studies reported the secondary outcomes cost of intervention, acceptability of the intervention (or satisfaction) with respect to patient comfort, length of patient hospital stay, surgical interventions, or osteomyelitis incidence.
One study exploring the impact of arginine, glutamine and β-hydroxy-β-methylbutyrate supplement versus placebo did not report on any relevant outcomes.